This application addresses PAR-09-247, Ancillary Studies to Major Ongoing Clinical Research Studies to Advance Areas of Scientific Interest within the Mission of the NIDDK, through an ancillary study of major gastrointestinal (GI) bleeding within five major ongoing epidemiological studies and clinical trials. Aspirin is widely used for prevention of cardiovascular events and other chronic diseases. However, GI bleeding is a potentially serious complication and the major limiting factor for aspirin use in clinical practice. Nearly 400,000 hospital admissions in the U.S. each year are due to GI bleeding with a mortality of 3% to 14%. Although the identification of patients at high risk of major GI bleeding i of major clinical importance, studies of risk factors for these events are limited. Most data deriv from retrospective case-control studies or registries with little information on aspirin use patterns, lifestyle factors, or bleeding from the small bowel or the lower intestinal tract. In addition, the association between clinical and lifestyle factors with genetic susceptibility and rik of GI bleeding have not been comprehensively explored. Thus, high quality, prospective data are needed to characterize more precisely the influence of clinical, lifestyle, and genetic factors on risk of aspirin-associated GI bleeding. In pursuit of these goals, we propose to examine clinical and lifestyle risk factors for major GI bleeding in the Nurses' Health Study (NHS), a cohort of 121,701 women, and the Health Professionals Follow- up Study (HPFS), a cohort of 51,529 men, each biennially followed with detailed questionnaires since 1976 and 1986, respectively. In parallel, we will investigate genetic risk factors for GI bleeding using a discovey- based approach leveraging existing genome-wide array data to identify novel genetic risk loci for GI bleeding in combination with a hypothesis-driven approach examining specific candidate genes. These prospectively collected, detailed data from two large cohorts over extended follow-up provide a unique opportunity to concurrently examine clinical, lifestyle, and genetic ris factors with risk of GI bleeding overall and according to anatomic and etiological subtypes. We will use these clinical, lifestyle and genetic risk factors to develop comprehensive risk predictio models and validate and characterize their performance within two independent population-based cohorts, the Framingham Heart Study (n=10,333) and the Oxford Vascular Study (n=91,106), and a completed randomized clinical trial of aspirin, the Physicians' Health Study (n=22,071). The identification of lifestyle and genetic risk factors for aspirin-associated GI bleeding would be of great clinical and public health significance as it may 1) improve risk stratification and clinical decision-making; 2) provide opportunities for risk modification; 3) infrm future guidelines regarding long-term aspirin use for disease prevention; and 4) guide the use of prophylactic therapy for the prevention of GI bleeding. With the growing use of aspirin for an expanding number of indications, our results may fulfill a critical unmet need for public health recommendations, individual clinical encounters, and future clinical trials of aspirin.